title: Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin.
abstract: OBJECTIVE
  We studied the safety and preliminary efficacy (marker tumor ablation) of 5 doses of BC-819 given as 6 intravesical infusions in patients with superficial bladder cancer in whom intravesical therapy with bacillus Calmette-Guerin had failed. BC-819 is a DNA plasmid that contains H19 gene regulatory sequences that drive the expression of an intracellular toxin.
  
  
  METHODS
  A total of 18 patients in 4 groups of 3 and 1 group of 6 received escalating doses of BC-819 intravesically during 7 weeks. Patients had low grade superficial bladder cancer, which expressed H19. The effect on a marker tumor was examined 12 weeks after starting treatment. The escalating doses were 2, 4, 6, 12 and 20 mg plasmid per intravesical treatment. Responders continued to receive BC-819 once monthly every month for 1 year.
  
  
  RESULTS
  No dose limiting toxicity was observed. The most frequent adverse events were mild to moderate bladder discomfort, dysuria, micturition urgency, urinary tract infection, diarrhea, hypertension and asthenia. Intravesical administration of BC-819 resulted in complete ablation of the marker tumor without any new tumors in 4 of the 18 patients for a 22% overall complete response rate. Eight of the 18 patients (44%) had complete marker tumor ablation or a 50% reduction of the marker lesion. Nine patients received monthly maintenance, of whom 4 and 1 were disease-free at 35 and 49 weeks, respectively.
  
  
  CONCLUSIONS
  Intravesical BC-819 causes tumor ablation following intravesical administration at doses that were well tolerated. It is worthy of continued clinical investigation.
authors.affiliation: Department of Urologic Surgery, Edith Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Holon, Israel. jransom@fasttrackresearch.com
authors.forename: Abraham Ami
authors.initials: AA
authors.lastname: Sidi
authors.forename: Patricia
authors.initials: P
authors.lastname: Ohana
authors.forename: Shalva
authors.initials: S
authors.lastname: Benjamin
authors.forename: Moshe
authors.initials: M
authors.lastname: Shalev
authors.forename: Janet H
authors.initials: JH
authors.lastname: Ransom
authors.forename: Donald
authors.initials: D
authors.lastname: Lamm
authors.forename: Avraham
authors.initials: A
authors.lastname: Hochberg
authors.forename: Ilan
authors.initials: I
authors.lastname: Leibovitch
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use; D004247:DNA / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D010957:Plasmids; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000096:biosynthesis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D004247:DNA